Variants in CDH23 cause a broad spectrum of hearing loss: from non-syndromic to syndromic hearing loss as well as from congenital to age-related hearing loss

Shin-Ichi Usami,Yuichi Isaka,Maiko Miyagawa,Shin-Ya Nishio

doi:10.1007/s00439-022-02431-2

Abstract

Variants in the CDH23 gene are known to be responsible for both syndromic hearing loss (Usher syndrome type ID: USH1D) and non-syndromic hearing loss (DFNB12). Our series of studies demonstrated that CDH23 variants cause a broad range of phenotypes of non-syndromic hearing loss (DFNB12); from congenital profound hearing loss to late-onset high-frequency-involved progressive hearing loss. In this study, based on the genetic and clinical data from more than 10,000 patients, the mutational spectrum, clinical characteristics and genotype/phenotype correlations were evaluated. The present results reconfirmed that the variants in CDH23 are an important cause of non-syndromic sensorineural hearing loss. In addition, we showed that the mutational spectrum in the Japanese population, which is probably representative of the East Asian population in general, as well as frequent CDH23 variants that might be due to some founder effects. The present study demonstrated CDH23 variants cause a broad range of phenotypes, from non-syndromic to syndromic hearing loss as well as from congenital to age-related hearing loss. Genotype (variant combinations) and phenotype (association with retinal pigmentosa, onset age) are shown to be well correlated and are thought to be related to the residual function defined by the CDH23 variants.

Highlights

The CDH23 gene, a member of the cadherin superfamily, encodes calcium-dependent cell–cell adhesion glycoproteins and is known to be expressed in both the inner and outer hair cells in the cochlea
Variants were defined as likely causative variants if the following criteria were fulfilled: (1) pathogenic or likely pathogenic based on the American College of Medical Genetics (ACMG) criteria, or (2) in the case of variants of uncertain significance (VUS) based on the ACMG criteria, where significant CADD scores (> 20) were observed, (3) biallelic variants found in recessive inheritance cases, (4) no other candidate variants were found and (5) there was no contradiction with the family analysis
The minor allele frequencies (MAFs) of these four highly prevalent variants in the Japanese and other ethnic groups are shown in Supplementary Table 1

Summary

Introduction

The CDH23 gene, a member of the cadherin superfamily, encodes calcium-dependent cell–cell adhesion glycoproteins and is known to be expressed in both the inner and outer hair cells in the cochlea. CDH23-related hearing loss has been reported in many countries with diverse ethnic backgrounds, including Cuba (Bolz et al 2001), Germany (Bolz et al 2001), Japan (Wagatsuma et al 2007; Miyagawa et al 2012; Mizutari et al 2015), Korea (Kim et al 2015, 2016), China (Lu et al 2014), India (Bork et al 2001; Ganapathy et al 2014; Vanniya et al 2018), Pakistan (Bork et al 2001; Park et al 2020), Saudi Arabia (Ramzan et al 2020), Iran (Zardadi et al 2020), Qatar (Alkowari et al 2017), Turkey (Atik et al 2015), Israel (Ashkenazi, Mizurahi, Sephardi) (Brownstein et al 2011), Palestine (Abu Rayyan et al 2020) and the Netherlands (Seco et al 2017)

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Discussion

Conclusion